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CONCLUSION Intravascular volume expansion with low molecular weight 6% HES did not appear to modify renal function, blood loss or transfusion when administered to children during the peri-operative period. However, given the lack of statistical power and the very low GRADE quality of evidence, more high-quality RCTs are needed to explore these outcomes.

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Introduction

Hydroxyethyl starches (HES) have been shown to be effective for intravascular volume expansion for more than 20 years. However, recently several studies have suggested a risk of renal, hepatic or haemostatic toxicity in adult patients who received HES in different clinical settings. Following three adult studies published in the New England Journal of Medicine between 2008 and 2012,1–3 the European Medicines Agency's Pharmacovigilance Risk Assessment Committee (PRAC) stated that HES should not be used in patients with sepsis, burns or critical illness but could still be used in patients with hypovolaemia caused by acute blood loss where treatment with crystalloids was not sufficient.4 The European Society of Intensive Care Medicine recommend that HES should not be used for volume expansion due to the high risk for inducing kidney injury and bleeding.5

Several meta-analyses confirmed that HES should not be used in sepsis,6–8 but some authors consider that the interpretation of the results of the studies cited in support of the conclusions of the PRAC did not take into account some methodological biases and the initial lack of studies in other situations such as peri-operative situations.9–12 This explains the persistence of a controversy about the effectiveness and side-effects of HES in adults.9,13–17 Conversely, during the peri-operative phase, recent studies18–26 and meta-analyses27,28 of adult studies continue to fuel the debate on HES administration.

There is much less data on the use of HES in paediatrics, with 11 studies reporting the efficacy and/or adverse effects of HES in the peri-operative child.29–42 In paediatric septic patients, one meta-analysis did not find any difference in mortality between colloids (including HES) and crystalloids.43 Until now there has been no meta-analysis evaluating the efficacy and safety of peri-operative use of HES in children. The objectives of this study were to evaluate the peri-operative (intra-operative and postoperative periods) efficacy and adverse effects of volume expansion using HES in paediatric populations. The choice of a meta-analysis over a systematic review was guided by the following considerations: first, the heterogeneity of studies would make it difficult to draw conclusions on outcomes, whereas a meta-analysis would allow a quantitative analysis as well as subgroup analyses to separately assess any effect of each confounding factor; second, meta-analysis with trial sequential analysis can assess if an outcome is correctly powered, as well as setting the number of patients to be included in future trials and meta-analyses.

Material and methods

Bibliographic search and analysis

We conducted this meta-analysis according to the Cochrane Handbook for Systematic Reviews guidelines, PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) statements and GRADE (Grading of Recommendations Assessment, Development and Evaluation) methodology.44,45 Search and statistical methodologies were similar to those used in meta-analyses previously published by some of the authors of the current study.46,47 There was no prepublished protocol for this meta-analysis.

Analysed literature databases included Pubmed, Embase, Cochrane central register of controlled trials, clinical trials register and open access journals not indexed in major databases (Directory of Open Access Journals, Open Journal of Anesthesiology, Anesthesiology Research and Practice, Journal of Anesthesia & Clinical Research, Journal of Anesthesiology and Clinical Science, Journal of Anesthesiology and Critical Care Medicine). The following key words associated with ‘neonate’ or ‘neonates’ or ‘infant’ or ‘infants’ or ‘child’ or ‘children’ and all key words ‘hydroxy ethyl starch’ or ‘HES’ or ‘hydroxystarch’ or ‘starches’ were used. Only articles written in English and French were considered.

Articles were independently analysed by four paediatric anaesthesiologists (double-checked results with cross-referencing when comparison between readers was assessed). Those fulfilling the following criteria were included in the analysis: randomised controlled study, double blinded (especially blinding of outcome assessment: evaluation of outcomes clearly stated to be performed by an operator blinded to the intravascular fluid used) and a standardised written anaesthesia protocol. Meeting abstracts were not included in this meta-analysis. These criteria allow us to select articles with the lowest methodological bias. The most recent search was December 2016.

Readers (two per article) assessed article quality and the presence of potential bias using the following criteria: randomisation, detailed description of methodology demonstrating whether intervention allocations could have been foreseen before or during enrolment, double blind study, incomplete data report statements (excluded patients and data), selective reporting (presence of studied outcomes report verified) and additional bias including the clear definition of main outcome and method used for calculating sample size to correctly power the study. Blinding of outcome assessment bias was considered as impacting overall results. Studies with risk of this bias – either undetermined or high-risk – were excluded from the analysis.

Extracted data consisted of the country where the study took place, registration of the study in a trial database, patient ages, ASA physical status, surgery performed, intravenous fluids used during the intra-operative period and outcomes relevant to this analysis. Outcomes were grouped into HES efficacy and HES adverse effects on renal and coagulation functions. Concerning HES efficacy, the amount of fluid administrated during the peri-operative period (the intra-operative period and the postoperative period up to 24 h) was considered the primary outcome, peri-operative (the intra-operative period and the postoperative period up to 24 h) administration of vasoactive drugs (24 h) and postoperative haemoglobin (Hb) levels (24 h) were secondary outcomes. Regarding renal toxicity, the primary outcome was considered to be peri-operative urine output (the intra-operative period and the postoperative one up to 24 h), and the secondary outcome the postoperative creatinine level at day 1. Finally, peri-operative (the intra-operative period and the postoperative one up to 24 h) blood loss was considered as the primary outcome of coagulation function. Secondary outcomes included the amount of packed red blood cells and fresh frozen plasma transfused during the peri-operative period (the intra-operative period and the postoperative one up to 24 h), and postoperative coagulation test results (activated prothrombin time: APTT, fibrinogen). Thromboelastographic data were not considered in this meta-analysis.

Statistical analysis

Classical meta-analysis procedures were performed using the Review Manager 5 software (RevMan 5.3; The Cochrane Collaboration, Oxford, United Kingdom) and the Trial Sequential Analysis (TSA) Software (Copenhagen Trial Unit's Trial Sequential Analysis Software; hereafter: TSA Software, Copenhagen, Sweden) to evaluate the effect of random error and calculate the information size (the power of the meta-analysis). For this meta-analysis, we calculated risk ratio or mean difference using the RevMan software and the cumulative z-score curve using the TSA software. To allow comparisons, all data were expressed as a weight ratio, by dividing both the mean and SD by the mean weight. Finally, a summary of primary outcomes results was analysed using the GRADE methodology [using the online GRADE pro software (https://gradepro.org/. Last access October 2016)] to allow clear recommendations regarding the impact of HES administration, in comparison with other intravenous fluids, on efficacy of intravascular filling, kidney complications and coagulation.

Heterogeneity was assessed using I2 statistics, which describe the percentage of variability in effect estimates (risk ratio, mean difference) due to heterogeneity rather than sampling error. According to the Cochrane review guidelines [http://www.cochrane-handbook.org/(Section 9.5.2). Last access April 2016], an I2 more than 40% and a P value less than 0.1 were considered as the threshold for heterogeneity and indicated the need for a random effect model. A random effect model was also considered where heterogeneous studies were included for analysis – either because of unstandardised intravenous fluid protocols or because of heterogeneous surgeries.

Subgroup analyses for the primary outcomes of this meta-analysis were also performed when at least two studies included the considered outcome. These analyses grouped patients according to the type of surgery performed (cardiac versus noncardiac surgery) and the control intravenous fluid (crystalloid, albumin or other colloids). These subgroup analyses allow assessment of the impact of surgery and of the administered fluids on studied outcomes, given that colloids are usually used as a priming solution during cardiac surgery. In addition, a sensitivity analysis was considered when data were published by authors suspected of misconduct. Although a more radical solution would consist of discarding these publications, this was not methodologically correct when articles are not retracted. Consequently, as previously performed in another meta-analysis, a sensitivity analysis, excluding studies suspected of misconduct, was performed.48 Comparison between subgroups (called the interaction test) was considered significant when the P value was less than 0.05. In studies with more than two groups, only the comparison between the HES and the crystalloid groups was considered.

Statistical methods are available to assess the effects of unpublished studies on the results of meta-analysis (publication bias) using the Funnel plot.49 Such asymmetry may also reveal data heterogeneity or poor methodology in included studies.49,50 According to the Cochrane collaborative guidelines [http://www.cochrane-handbook.org/ (Section 10.4.3.1). Last access April 2016], publication bias can be assessed when analysis aggregates at least 10 studies.

A second set of analyses was performed for the primary outcome of each endpoint using TSA.51,52 This method has been found to be more relevant when analysing cumulative heterogeneous results and decreases type I error. TSA provides three important complementary data points when compared with traditional meta-analysis. First of all, it combines results and provides a cumulated sample size of included trials using an approximate semi-Bayes procedure with an adjusted threshold for statistical significance and adjusted alpha risk to decrease type I error. The second information is the effect of previous meta-analyses on overall results. Considering that the alpha risk must be adjusted to the number of comparisons, classical meta-analysis does not take into account this correction (leading to 20 to 30% of false-positive results),51 whereas TSA can perform corrections according to studies previously included in previous meta-analyses. Lastly, TSA allows the description of further trial requirements, through a procedure known as trial sequential monitoring boundaries. When the cumulative z-scores for the studied outcome cross the trial sequential monitoring boundary, the level of evidence for the intervention is considered reached and no further trials are needed. TSA also determines the futility area, indicating that no significant result would be found with additional trials. Finally the O’Brien–Fleming approach using the TSA (the number of patients to be included in the meta-analysis to reach the desired level of power) predicts the sample size to be included in future trials to achieve the desirable effect (according to current results) with sufficient statistical power. In our study, information size (number of patients to be included to fulfil alpha and beta risks) was computed for the primary study outcome assuming an alpha risk of 5%, a beta risk of 20% and a relative risk difference between HES and other fluids computed on the mean difference obtained using the classical meta-analysis method.

Finally, a summary of overall analyses was processed using GRADE analysis. To assess the overall quality of evidence for each outcome (pooled data expressed as risk ratio, mean difference), we downgraded the evidence from ‘high quality’ by one level in the following circumstances: high-risk bias in included studies, indirectness of evidence, serious inconsistency (either heterogeneity or the use of a random statistical model), imprecision of effect estimates, potential publication bias (if number of included studies allow assessment) and the potential lack of power of analyses.53–56 Data from RevMan software were transferred in the GRADEPRO online program (https://gradepro.org/. Last accessed October 2016).

Results of intervention effects were expressed as risk ratio, mean difference or standardised mean difference (SMD) [95% confidence interval (CI)], I2, P value for I2 statistics, number of trials for the outcome, number of patients and level of GRADE recommendation.

Results

Overall, 351 reports from the literature were found from which 342 studies were excluded after reading the title, the abstract and/or the full text. All data extracted were displayed as numerical values except for values that were graphically extracted in some studies.29–31,35,37 Finally, nine randomised controlled trials (RCTs) were included in the study (flow chart: Fig. 1). The characteristics of included trials are displayed in Table 1. Bias was found in all studies and consisted in most cases in an undetermined risk or high risk of biases (Supplementary file 1, http://links.lww.com/EJA/A140). Some studies did not display a primary outcome or did not clearly explain the method used to compute the sample size for the main outcome (Supplementary file 1, http://links.lww.com/EJA/A140). One study was published by an author who was suspected of misconduct (Boldt).29 Data were all extracted for the period covering the first postoperative day, consequently outcomes concern this period.

Trial sequential analysis

TSA for total fluid intakes on day 1 (Fig. 4a) found that HES had no significant effect on this outcome when compared with other fluids and the z-curve did not cross the trial sequential monitoring boundary, indicating that this effect remains uncertain. Moreover, the calculated correctly powered sample size would be 546 patients for detecting a decrease in the total fluid intake at day 1 of 5 ml kg−1 when using the HES instead of another solution. Consequently, this meta-analysis appears underpowered to analyse this outcome given that only 321 patients were analysed for this specific outcome.

Concerning urine output on day 1 (Fig. 4b), TSA confirms the results of classical analysis (using mean difference or SMD); however, the z-curve did not cross the trial sequential monitoring boundary defining a significant result. Computing information size with an expected difference between the HES group and the control one of 7 ml kg−1 (the difference found when computing the mean difference), at least 504 patients would need to be included to correctly power analysis. Only 196 patients were included in the analysis of this specific outcome.

Concerning blood loss on day 1 (Fig. 4c), the classical approach using the mean difference and TSA obtained the same results. The information size could not be calculated for this outcome.

Finally, knowing that our meta-analysis was the first performed on this specific topic, no correction for the alpha risk was required.

Study bias analyses

Except for the study by Van der Linden et al.36, all other studies presented with at least one risk of bias. Consequently, all results displayed in the current meta-analysis have to be interpreted cautiously.

Subgroup analyses

Subgroup analyses displayed similar results to the overall results except for the total fluid intakes on day 1, which were significantly less in the subgroup of studies performed in noncardiac surgery (Table 2).

GRADE analyses

In accordance with GRADE recommendations, the following adjustments were performed: one level downgraded for bias of included studies (considered as serious), one level downgraded for inconsistency of results (considered as serious: because of heterogeneity of results or the random effect model used) and one level downgraded for lack of power of the analysis concerning the primary outcome.44,45,53–59 Consequently, all primary outcomes of this meta-analysis were graded as ‘very low level of evidence’ (Supplementary file 2, http://links.lww.com/EJA/A140).

Discussion

The current first meta-analysis on the effects of peri-operative HES in children undergoing both cardiac and noncardiac surgery did not find any significant difference between HES and control solutions for the following outcomes: the decrease of amount of intravenously administered solutions, renal function, coagulation function and blood loss. In a subgroup analysis of patients undergoing noncardiac surgery, the efficacy of HES was found to be slightly superior to control solutions given that the total amount of fluid was significantly decreased when using HES. However, the current meta-analysis lacked power to show any difference (as suggested by trial sequential analyses) and the level of evidence grades were very low.

In adult patients, it is now clear that HES should not be used in septic patients. Evidence against their use during the peri-operative period is less strong.25,60–64 In addition, meta-analyses performed on adult studies did not show any significant differences between HES and other fluids. However, the heterogeneity of results, the lack of good quality studies and the lack of power (as suggested by trial sequential analyses) of these meta-analyses clearly impair their level of evidence. As a result, no clear conclusions can be drawn concerning the safety of HES.27,28 Regarding critically ill children, apart from platelet count and duration of ICU stay, no adverse effects of HES have been described and, in particular, no renal impairment.38,65 However, one of these two reviews focused on exotic clinical situations where studies were performed during dengue shock syndrome and severe malaria, which clearly limit their generalisation to the peri-operative period. The second meta-analysis, more close to ours from a clinical point of view, nevertheless included patients following cardiac surgery, that is a more restrictive clinical situation with consequently fewer patients than in the current review.66–70

During the peri-operative period, our meta-analysis showed that HES was associated neither with significant reductions in urine output nor with significant increases in serum creatinine levels. This result is in accordance with conclusions of a previous meta-analysis in paediatric patients.65 However, given the wide CIs of results, the small sample size and the low level of evidence, our study cannot definitively conclude regarding potential renal adverse effect in paediatric patients. Considering these limitations and the strong evidence of an association between HES use and an increased incidence of acute kidney injury in adult patients,7,71,72 it appears reasonable to suggest that HES should not be used in paediatric patients with pre-existing renal dysfunction.

Our meta-analysis did not show any significant difference in effect between HES and other fluids on blood platelet counts or coagulation test results in surgical paediatric patients. Moreover, bleeding was similar between patients receiving HES and those receiving other solutions. This result was different to the meta-analysis performed by Li et al.65 who reported decreased platelet counts in critically care patients. Although, many studies have not observed any significant change in prothrombin time and APTT following HES administration in paediatric patients,33,34,73 Haas et al.32 reported impairment in thrombelastometric parameters and global coagulation tests following HES administration in comparison with albumin or gelatin solutions. Moreover, Miller et al.74 also reported increased blood loss associated with the use of HES after cardiopulmonary bypass in paediatric patients. There is a strong association between coagulation disorders and peri-operative bleeding, especially during cardiac surgery.75,76 Summarising our results and the available literature, a detrimental effect of HES on haemostasis could not be excluded, especially during cardiac surgery.

Despite the potential adverse effects of HES, one should be aware that crystalloids have adverse effects.77–81 The use of 0.9% saline is associated with hyperchloraemic metabolic acidosis and renal dysfunction, and hyperchloraemia is independently associated with increased mortality after noncardiac surgery.81 Therefore, physicians should be aware that all intravenous fluids should be considered medicines capable of producing adverse effects, especially if recommended indications, contraindications and maximum dosages are not respected.

The beneficial effects of HES are poorly documented in the current study. However, subgroup analysis found a slight but significant decrease in the total volume of peri-operative fluids administered in children receiving HES during noncardiac surgery. This result should be interpreted in the light of previous studies with comparable outcomes. Many trials have demonstrated improvements in urine output, increases in left ventricular ejection fraction, lower requirements for vasopressors, as well as a better fluid balance pattern with a reduced risk of fluid overload and an improvement in liver perfusion, when comparing HES with crystalloids,78–80 and some of the trials include paediatric patients. Thus, more studies are needed to explore the benefits of using HES in children, especially in noncardiac surgery.

Our meta-analysis also shows that there was no significant difference between HES and human albumin, regarding efficacy or side-effects. The lack of proven superiority of human albumin over HES, its high cost and the potential risk of contamination by an unconventional transmissible agent make the routine administration of human albumin for vascular loading highly questionable in the peri-operative period in children.

There are several limitations to this meta-analysis and caution must be used in the interpretation of the results. First, the analysis is based on only nine RCTs and some of them included a relatively small sample size of paediatric patients. One study by Haas et al.32 was excluded because of the use of interquartile range, which cannot be correctly included in meta-analyses. Second, control groups in the included studies used a variety of fluids including fresh frozen plasma, human albumin, gelatin and crystalloids. However, subgroup analyses (Table 2) were performed according to the specific fluid used in the control group to investigate effects of this factor on results (with unchanged conclusions in comparison with overall results). Third, there was substantial heterogeneity in included studies, including in patient characteristics (e.g. age and other baseline data), which may have affected results. Fourth, one study performed by Boldt was included in analyses given the absence of retraction of this work from valid literature. Of note, a previous meta-analysis performed by Zarychanski et al. found Boldt's studies to influence overall results.48,82 Consequently, sensitivity analyses were performed to assess the impact of this study on overall results of our meta-analysis. Although, the study performed by Boldt did not impact the directness of our results, overall quantitative effects might have been impacted by including this effect. Fifth, renal function was assessed using poorly sensitive renal biomarkers, such as urine output or plasma creatinine levels. There was an insufficient number of studies assessing renal function with more accurate and sensitive renal biomarkers, such as α-1-microglobulin, N-acetyl-β-d-glucosaminidase or neutrophil gelatinase-associated lipocalin. However, a recent systematic review reported that there is currently no indication in the literature that the use of tetrastarches induces adverse renal effects in surgical adult patients.39

Conclusion

The current meta-analysis, with its included efficacy and various safety analyses, demonstrates no relevant differences between HES and control fluid groups. There was no significant increased renal toxicity of HES compared with other solutions, during both cardiac and noncardiac surgery in children. The relatively small number of studies (and numbers of patients within these included studies), the high heterogeneity of results, the lack of power of this meta-analysis and the very low grade of evidence preclude any firm conclusions regarding safety and efficacy. As a consequence, paediatric anaesthesiologists are urged to perform more studies to elucidate the role of HES in the peri-operative paediatric patient population.